Noninvasive Screening for Coronary Artery Disease With Computed Tomography Is Useful
2006; Lippincott Williams & Wilkins; Volume: 113; Issue: 1 Linguagem: Inglês
10.1161/circulationaha.104.478354
ISSN1524-4539
Autores Tópico(s)Advanced MRI Techniques and Applications
ResumoHomeCirculationVol. 113, No. 1Noninvasive Screening for Coronary Artery Disease With Computed Tomography Is Useful Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessArticle CommentaryPDF/EPUBNoninvasive Screening for Coronary Artery Disease With Computed Tomography Is Useful Melvin E. Clouse, MD Melvin E. ClouseMelvin E. Clouse From the Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass (M.E.C.); Section of Cardiology, Department of Medicine, Beth Israel-Deaconess Medical Center, Boston, Mass (J.C.); and the Sections of Cardiovascular Medicine, Department of Medicine; Health Policy and Administration, Department of Epidemiology and Public Health; and Robert Wood Johnson Clinical Scholars Program, Department of Medicine, Yale University School of Medicine, and Center for Outcomes Research and Evaluation, Yale-New Haven Health, New Haven, Conn (H.M.K.). Originally published3 Jan 2006https://doi.org/10.1161/CIRCULATIONAHA.104.478354Circulation. 2006;113:125–146The introduction of new ideas and concepts that lead to change in practice has always caused some degree of controversy, especially in medicine. At first glance, the concept of noninvasive imaging for calcium as a screen to identify patients at high risk for future coronary events would seem the most intense; however, one must only reflect on past controversies to gain an appropriate perspective. The controversy over radical mastectomy versus segmental resection or lumpectomy with radiation therapy has raged for the past 50 years, and only recently have data from the 20-year follow-up of a randomized trial comparing these forms of treatment been put forward.1,2 The process of establishing the chest roentgenogram as a standard diagnostic method in the diagnosis of respiratory disease spanned 30 years and was opposed by many of the leading physicians of the day, including Osler,3 who believed a good clinical examination was superior. In 1915, Crane4 stated that the chest roentgenogram that "claims a delicacy, rapidity and precision outranking the stethoscope and the percussion finger must expect to run a gauntlet of merciless criticism." The chest roentgenogram largely came into general use in the 1930s, when it was recognized that &15% of the deaths in the United States were due to tuberculosis, and a massive screening process was instituted after World War II.5 Establishment of the chest roentgenogram as a diagnostic tool was based largely on the belief in technology and innovation; to date, however, no prospective randomized studies have been conducted to determine whether the chest roentgenogram has indeed affected the outcome of patients with cardiopulmonary diseases. Thankfully, the coronary artery calcium (CAC) examination has been placed under intense scrutiny, and although the construct and ethics of a prospective randomized study have yet to be decided, it is appropriate to review and discuss how it may help in treating patients with subclinical atherosclerosis and to determine its absolute predictive value and its relationship to the Framingham Risks score and National Cholesterol Education Panel Adult Treatment Panel III (NCEP ATP III) guidelines because it is the only noninvasive test available to evaluate insults to the arterial wall from all risk factors causing atherosclerosis.The concept of imaging coronary arteries for calcification in vivo arose shortly after the discovery of x-rays by scientists who demonstrated calcification within the coronary arteries but were limited by current technology.6–8 After publications by Habbe and Wright9 and Van der Straeten,10 Blankenhorn and Stern, in a landmark article, scientifically established the fact that calcification in the coronary arteries is directly related to atherosclerosis.9–13 Recent studies have confirmed that the development of arterial calcification is intimately associated with vascular remodeling and atherosclerotic plaque and is controlled largely by cellular and subcellular mechanisms.14–17 Histopathological studies have also shown that calcification is found more frequently in advanced atherosclerotic plaque and is associated with plaque in larger arteries than in peripheral coronary arteries.18–20 In 1903, Monckeberg described calcification that occurs in the media, usually in the peripheral and visceral arteries and only occasionally in the coronary arteries, and is not associated with atherosclerosis.21Historically, cardiac fluoroscopy was frequently used to detect calcium in the coronary arteries because it was much more sensitive for detecting calcium than the standard chest roentgenogram. In 1987, Detrano and Froelicher22 summarized studies involving 2670 patients undergoing coronary arteriography and equated the findings of calcification for detecting significant stenosis (>50% diameter) with a sensitivity of 40% to 79% and specificity of 52% to 95%. That same year, Reinmueller and Lipton23 studied a small group of patients and demonstrated that CT was much more sensitive for detecting calcification than fluoroscopy (62% versus 35%). However, image quality was degraded by cardiac motion.The new era for imaging CAC began with the introduction of the high-speed cine-CT scanner. The cine-CT/ultrafast CT scanner, later designated the electron-beam CT (EBCT), performed 3-mm-thick cross-sectional slices in 50 to 100 ms with exposure gated to 80% of the R-R interval. Thus, the heart could be examined in a single breathhold with the x-ray beam passing from the source through the body to a detector array; the recorded data were transformed through a filtered back-projection reconstruction technique into 2D images.Agatston et al,24 guided by a method originally conceived by David King (Imatron), used the EBCT to quantify CAC, working on the premise of using the calcium score as an independent predictor for future myocardial events, as indicated by Margolis et al25 in 1980. They established the scientific basis for the scoring system based on an x-ray attenuation coefficient or CT numbers measured in Hounsfield units by selecting the maximum calcium density within the area. The area of calcium was calculated from the field of view and the image matrix that, on the standardized protocol, relate to 3 pixels or 1 mm2 with a density of 130 Hounsfield units. Statistical analysis was performed on the log-transformed total score and on the square root of the number of lesions to normalize the data. After completing a scan with the same parameters using a high-resolution volume mode with 3-mm-thick slices, they repeated the same scan in a single-slice mode with 20 and then 40 contiguous slices throughout the heart with no interslice gaps. Callister et al26 improved the reproducibility of the calcium score, especially in the lower ranges, by introducing the volume score (isotropic interpolation) method.The ability to identify individuals at high risk and thus to direct appropriate therapies to prevent further myocardial events would be a great benefit to society because cardiovascular disease is the most important health problem in America and the Western world, accounting for 38.5% of all deaths. The death rate from cardiovascular disease is greater than the second through the seventh leading causes of adult death, including cancer, AIDS, accidents, homicides, infections, and diabetes mellitus. The total cost for treating far-advanced, ie, end-stage, cardiovascular disease is enormous. The estimation has increased from $286.5 billion in 1999 to $368.4 billion in 2004, accounting for a third of the cost of our $1 trillion healthcare economy. The cost for physician care and testing is only 10% ($31 billion), with the remainder being for patient care.27,28 The current methods of diagnosis and treatment have had little effect on the outcome of a disease that is largely preventable with institution of strict risk factor modification and statin therapy if discovered early.29–34 Up to 50% of patients with atherosclerotic disease present with either ischemic heart disease or sudden death, and for 150 thousand individuals, a fatal heart attack is the first symptom of heart disease.27,28 Fifty percent of these myocardial infarctions (MIs) occur in patients with no prior history of disease, and 68% of these are due to lesions representing a stenosis diameter <50%. Cholesterol is perceived as one of the most important risk factors for coronary artery disease, but &35% with established heart disease have total cholesterol levels <250 mg/dL; thus, cholesterol has failed to predict up to one third of future deaths resulting from coronary artery disease. In a recent study, 204 men <55 years of age and women <65 years of age presenting with acute MI had cholesterol tests performed within 12 hours of admission. Sixty-eight percent had LDL cholesterol levels <131 mg/dL, 41% had LDL cholesterol levels 130 mg/dL. Only 25% of these patients, all of whom subsequently suffered MI, would have qualified for lipid-lowering therapy under the current NCEP ATP III guidelines.35Comparison of EBCT CAC Score With Other Noninvasive TestsPatients with typical angina/symptoms of coronary heart disease normally undergo routine noninvasive tests such as exercise ECG, echocardiography, myocardial scintigraphy, or pharmacological stress tests. These tests are used when patients are symptomatic with far-advanced disease, are based on indirect signs of atherosclerosis that result from inadequate myocardial perfusion, and have a high pretest probability of being positive.The consensus statement reports on a large meta-analysis with high sensitivities, specificities, and accuracy for the exercise treadmill test (ETT) in the range of 68%, 77%, and 73%, respectively, for ECG; 89%, 80%, and 89% for myocardial perfusion; and 85%, 84%, and 87% for pharmacological scintigraphy/echocardiography compared with 91%, 49%, and 70% for EBCT.36 Others give lower and more variable sensitivity and specificities of 85% to 77% for echocardiography, 87% to 63% for myocardial scintigraphy, and 84% to 44% for pharmacological treadmill testing, depending on the number of vessels involved.37–39 Such results are influenced by gender, age, cardiac rhythm, and inability to exercise.Haberl et al,40 like most investigators, reported a higher sensitivity and specificity and less variability for EBCT. With cut points for calcium scores of >20th, >100th, and >75th percentile of age groups, the sensitivity for detecting stenoses decreased to 97%, 93%, and 81%, respectively, for men and 98%, 82%, and 76% for women. Specificity increased up to 77% for both. Sensitivity and specificity are related to the cut points for the calcium score for which there currently is no agreement. The negative predictive value for a zero calcium score was 99%.40 Kajinami et al41 also reported an overall accuracy of 85% for EBCT compared with 71% for myocardial scintigraphy.Regardless of the variability of the reported data, the ETT/myocardial perfusion tests provide a high accuracy for predicting future myocardial events.42 Therefore, they are an essential part of the diagnostic armamentarium. They are performed to detect the possibility of flow-limiting lesions (far-advanced disease) but when negative give no information as to the presence of significant plaque burden and do not identify patients with subclinical atherosclerosis who may be at risk for future myocardial events, thereby alerting the patient/and physician to vigorously pursue preventive measures. Therefore, the calcium examination should be used in low-yield situations such as atypical chest pain to screen and possibly reduce the number of patients subjected to invasive procedures when the above noninvasive tests are not conclusive. Intravascular ultrasound is a more accurate method for plaque evaluation, but its usefulness in routine clinical decision making is limited because of its invasive nature.CAC ScoringTo be used effectively, EBCT CAC must be validated. How accurate is it for identifying calcium? How reproducible is the score? What variation is there between 2 scans taken several minutes apart in the same patient? The reproducibility and variability of the EBCT calcium score have been studied extensively. Earlier reports have shown significant variability, between 14% and 38%; however, these imaging algorithms are no longer up to date. Previously, the limitations on slice number, suboptimal gating, and table motion led to higher interscan variability. Hardware for EBCT has improved significantly, and there has been marked improvement in the reproducibility of the calcium score. A recent study of 1311 asymptomatic individuals undergoing 2 scans 3 minutes apart resulted in an average interscan variability of 15% to 17%.43 Another study using a newer protocol demonstrated a mean interscan variability of 16% to 19% and a median variability of 4% to 8.9% for the Agatston and volumetric scores.44 There was also significant improvement in the quantification of calcium score with the introduction of the volumetric method. The inherent issue of cardiac motion will continue to be a problem, especially for the right coronary and left circumflex arteries.45,46 Several investigators have suggested triggering exposure to 40% of the R-R interval and have reported an interscan variability of 11.5%. However, others have not found this necessary.44Multirow detector computed tomography (MDCT) has recently been introduced for CAC scoring. Investigators have found significant interscan variability and reproducibility with single-slice scanners at rotational speeds of 800 ms. The variability has been most marked using densities of 90 rather than 130 Hounsfield units.47 MDCT technology for CAC scoring is improving rapidly. Initial reports were from dual and 4-slice scanners with variabilities of 25.2% for overlapping images with volume scoring and 45.5% for Agatston scoring.48 MDCT scanners can image a section of the heart simultaneously with ECG gating in either the prospective (ECG triggering) or retrospective mode for segmented reconstruction. This allows a gapless helical scan of the entire heart. Prospective gating usually produces 3-mm-thick slices with a temporal resolution of 200 or 250 ms. Temporal resolution of 100 to 125 ms can be achieved with the retrospective mode with overlapping slices but with a marked increase in radiation dose. Now, 4-MDCT and 8-MDCT scanners are being replaced with 16-MDCT scanners. Reconstruction algorithms have improved with retrospective gating. Furthermore, we can expect 32- and 64-MDCT scanners to have rotational speeds of 330 ms, which will allow temporal resolutions of 175 or 87 ms to improve resolution and to reduce cardiac motion.A recent study of 32 patients demonstrated a variability of 20.4% for Agatston scoring and 13.9% for volumetric scoring for MDCT.49 Another recent publication comparing MDCT with EBCT shows high correlation of scores at every calcium level and similar areas under receiver-operating characteristic (ROC) curve.50 A more recent report of 100 patients undergoing both MDCT and EBCT shows similar sensitivity and specificity of 98.7% and 100%, respectively. The variability of the volume score was 20%; the mass score was 20.3%.51There is significant discussion as to the most appropriate scoring method, ie, Agatston, volume, and mass scores. However, regardless of imaging technology and methods of obtaining and measuring calcium score, the Agatston method is the standard now and for the foreseeable future. This is predicated on the significant available database for these scores and outcomes data currently in use because clinicians know the significance of a certain score using the Agatston method. Volume scores are similar, although slightly lower, and mass scores are significantly lower. Almost all scoring software now gives all 3 scores simultaneously for each subject; therefore, all are readily available.Radiation DoseRadiation dose for CT scanning is significant, and every effort is being made to reduce the dose. MDCT scanning is usually performed with prospective gating with 3-mm slice thickness. The effective radiation dose for MDCT scoring was 1 to 1.5 mSv for men and 1 to 1.8 mSv for women using 100 to 140 mA and 140 kV. The equivalent dose for EBCT is 0.7 to 1.0 mSv for men and 1.3 mSv for women. These dose rates are based on prospective triggering rather than retrospective triggering using thinner overlapping slice segments that improve spatial resolution.52 To reduce radiation exposure using these retrospective gating algorithms with 4-MDCT, Mahnken et al53 report an effective radiation dose of 3.01 mSv (range, 2.5 to 4.18 mSv) for men and 4.44 mSv (range, 3.28 to 5.88 mSv) for women. Trabold et al54 and Flohr et al55 report dose rates for 16-MDCT that are similar to the previous MDCT scanners. Hirota et al,56 however, report effective dose rates with gated studies of 2.6 and 4.1 mSv using 100 and 150 mA and 120 kV, respectively. The dose rates for CT coronary arteriography are much higher, 9.3 and 11.3 mSv using 300 mA. Most investigators did not use β-blockers to reduce heart rate and cardiac motion. Although both EBCT and MDCT have inherent limitations using 100- and 200-ms exposures, EBCT (e-speed) does image at 50 ms, if needed, for high resolution. Reducing the heart rate from 75 to 65 bpm increases the diastolic phase from 530 to 620 ms, whereas the systolic phase is increased only from 270 to 300 ms. Scanning at a lower heart rate would significantly reduce the in-plane motion of the coronary arteries; however, a significant number of patients will have heart rates >75 bpm, which may predicate the use of retrospective gating.Significance of CACRecent reports have confirmed that atherosclerosis is the only disease associated with coronary calcification and that calcification is intimately associated with plaque.14,18,36,56,57 CAC is an active process seen in all stages of plaque development. It is strongly correlated with age and increases significantly after 50 years of age. It parallels the prevalence of atherosclerotic plaque development as demonstrated by intracoronary ultrasound, which shows significant noncalcified plaque of 17% in 20-year-old individuals, increasing to 85% in individuals >50 years of age.58 The EBCT calcium score follows the same pattern of calcification in all age groups and progresses rapidly after 50 years of age.59 There is a slight gender variation in women, with lower scores in the early decade, but this is eliminated in the 65 to 70 years of age group.60The correlation of plaque calcification within noncalcified plaque as demonstrated by EBCT was established by Simons et al57 and Rumberger et al61–63 with excellent histological studies on randomly selected hearts quantifying CAC and total plaque by measuring direct histological plaque area and percent luminal stenosis. These studies demonstrated that the calcium score correlated linearly with total plaque area and that calcified plaque accounted for only 20% of the total plaque burden. In addition, a calcium area 1 mm in diameter predicted mild stenosis, whereas a calcified area of 3 mm was more likely to be associated with significant luminal narrowing. These studies also noted that calcium is a reflection of total plaque burden but that the calcium score does not translate in a one-to-one fashion to direct luminal narrowing. A study by Sangiorgi et al64 suggests that this is related to the remodeling phenomenon reported by Glagov et al.65 Baumgart et al63 confirmed the direct association of CAC score with hard and soft plaque using intracoronary ultrasound and arteriography. For plaques with and without calcification, the sensitivity was 97% and 47% and specificity was 80% and 75%, with an overall accuracy of 82% and 69% respectively, thus confirming the high sensitivity for detecting calcium and the high negative predictive value of a negative EBCT score.63In addition, EBCT has demonstrated its ability to quantify atherosclerotic plaque and, by virtue of the score, measure the severity, ie, stage of disease, in the coronary artery in direct comparison to pathological studies, regardless of age and gender.61,62 The scores are reproducible and interscan variability is sufficient for use in research and clinical studies. The 4-, 8-, and 16-MDCT scanners have been shown to be comparable with respect to quantifying the calcium score.The most important application of the EBCT CAC examination is the high negative predictive value of a zero CAC score. It indicates that no calcium is present. It also indicates that there is little likelihood of significant arterial stenosis (negative predictive value, &95% to 99%). A negative score is consistent with a low risk for hard coronary event (0.1% per year) or any event in the next 2 to 5 years.36,57Although there may be controversy over the use of the calcium score to diagnose obstructive disease, there is little controversy in its ability to detect calcified plaque. The ability of the CAC to estimate total plaque burden, ie, stage of disease, is the most significant predictor for future myocardial events.66 Therefore, the importance of the CAC score lies in its ability to identify individuals at risk and to integrate this information with other risk factors for risk stratification and goal-directed prevention.CAC as a Predictor for Future Myocardial EventsIt has long been known that CAC is related to atherosclerosis, and individuals dying of coronary artery disease have significantly more calcification than that seen in age-matched control subjects.67 In addition, calcification is the best indicator for severity, ie, stage of the disease. It would seem intuitive that calcification represents the sum total of insults to the arterial wall from all risk factors. It therefore should be an important predictor for future myocardial events and should be compared with the standard risk factors and NCEP guidelines. It is also known that a major portion of acute ischemic cardiac events occur from rupture of vulnerable plaques that are hemodynamically insignificant in asymptomatic individuals. Thus, it is important to evaluate the significance of CAC as a predictor for future myocardial events.Five recent studies have evaluated the significance of CAC as a predictor for future myocardial events since the initial article by Arad et al68 in 1996. These articles have been selected for this review and include data from a total of 17 976 subjects who were self-/physician referred and 6897 prospectively enrolled for EBCT CAC studies. The mean age varied from 52 to 59 years; 51% to 79.45% were men, and 20.6% to 49% were women. The participants were asymptomatic with no prior history of coronary artery disease. In the self-/physician-referred group, most were 40 to 70 years of age, with equal numbers 70 years of age. In the St Francis Heart Study (SFHS), the mean age was 53±11 years; in the South Bay Heart Watch Study (SBHW), the mean age was >45 years, and most had at least 1 abnormal risk factor that would place them in the intermediate- to high-risk category for Framingham Risk Score (FRS)/NCEP ATP II guidelines (>10% estimated 8- to 10-year risk for developing coronary heart disease [CHD]). On evaluation, the conventional risk factors were reported to be in the range of 45% for hypertension, 10% for diabetes, 60% for hypercholesterolemia, and 40% for smoking. The mean follow-up was 32±7 to 51±9 months in the self-/physician-referred group and 4.3 and 8.5 years for the SFHS and the SBHW groups, respectively.The first publication to assess the potential predictive value of CAC for future myocardial events was an analysis of 1173 in a 19-month follow-up that reported sensitivities of 89%, 89%, and 50% (inadequate number of subjects) and specificities of 77%, 82%, and 95% for calcium scores of 100, 160, and 680, respectively. Odds ratios (ORs) ranged from 20.0 to 35.4 (P 160 and <160 were associated with an OR of 15.8 and 22.2, respectively. Hard coronary events progressed with increasing CAC scores (P<0.0001).69 Raggi et al70 compared a group of 172 patients who had EBCT imaging within 60 days of an unheralded MI with 632 self-/physician-referred asymptomatic patients with a 32±7-month follow-up. The groups' demographics, including age and calcium scores, were similar. The annualized event ranged from 0.09 to 1.05 (12-fold difference) between the lowest and highest quartiles in patients identified by conventional risk factors and 0.045 to 2.7 (59-fold difference) when grouping was done according to CAC quartiles, indicating that although standard risk factors are important, CAC percentiles are substantially more important for identifying patients at risk.70 In a previous study, these same authors, analyzing 676 patients and using 10 122 asymptomatic patients as control subjects, demonstrated that CAC score percentiles were a significant predictor for coronary events and incrementally added to the prognostic value of traditional risk factors for CAD (P<0.001). Area under the ROC curves for hard events, when added to conventional risk factors, was significantly larger than conventional risk factors alone as predictors (0.84 versus 0.71; P<0.001). The area under the curve using CAC score percentiles alone was significantly greater than conventional risk factors (0.82 versus 0.71; P=0.028). The authors conclude that age- and sex-specific CAC score percentiles provide the best predictive model and add incremental predictive information to conventional risk factors.71Kondos et al72 reported on a group of 5635 asymptomatic patients (64% response). The mean age was 59±9 years, with a follow-up of 37±13 months. The prevalence of CAD risk factors was less than reported in the National Health and Nutrition Survey (NHANES) and Atherosclerosis Risk in Communities (ARIC) except for hypercholesterolemia, which was higher. Using univariate and multivariate analysis comparing those with and without events demonstrated that increasing age, smoking, diabetes, and hypertension were all significant (P 170 (RR, 7.24; 95% CI, 2.01 to 26.15) of developing a hard coronary event compared with those without CAC. In another large study of 10 377 self-/physician-referred patients, the authors demonstrated that the 5-year risk-adjusted survival was 99.0% for a CAC score 1000 (P<0.001).73 The area under the ROC curve of 0.72 for conventional risk factors increased to 0.78 when CAC scores were added to the model (P 270 compared with 0) for hard coronary events was 4.5 (P<0.05) and 8.8 for soft events (P 100 predicted all cardiovascular events, all coronary events, nonfatal MI, and coronary deaths with an RR of 9.5 to 10.7 at 4.3 years compared with a score of 45 years of age with at least 1 abnormal risk factor (>10% estimated risk for developing CHD by early Framingham risk equation) selected from a community mailing campaign. Beginning in 1992, the investigators began using EBCT. An early report by Secci et al,76 who selected 326 of 462 original study participants, noted after a follow-up of only 2.7 years that the prediction of nonfatal MI and death based on the calcium score did not reach statistical significance (OR, 3.1; P=0.07).76 Detrano et al77 later reported on the same SBHW group of 1196 asymptomatic high-coronary-risk subjects with a mean age of 66 years. The ROC curves from the Framingham model, their own data-derived risk model, and the CAC score were 0.69±0.05, 0.68±0.05, and 0.64±0.05, respectively (P=NS), demonstrating that the EBCT, although no better a predictor than FRS, nevertheless was equal to the sum of all risk factors in predicting cardiac events. This report was a major factor for the final report from the ACC/AHA consensus document largely because of the incomplete representation of the data.36 The ACC/AHA panel neglected to mention that the Detrano group also did not find the Framingham risk model to be a
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